Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels—Brief Report. Issue 1 (January 2021)

• Record Type: Journal Article
• Authors: Hoekstra, Mary; Chen, Hao Yu; Rong, Jian; Dufresne, Line; Yao, Jie; Guo, Xiuqing; Tsai, Michael Y.; Tsimikas, Sotirios; Post, Wendy S.; Vasan, Ramachandran S.; Rotter, Jerome I.; Larson, Martin G.; Thanassoulis, George; Engert, James C.
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 41:Issue 1(2021)
• Publication Date: 2021-01
• Subjects: atherosclerosis -- cardiovascular diseases -- genome-wide association study -- lipoprotein(a) -- risk factors; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.120.314965
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : Objective: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance (P ⩽5×10 -8 ). In addition to validating previous associations at LPA, APOE, and CETP, we identified a novel variant at the APOH locus, encoding β2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047–0.081]; P =2.8×10 -13 ) and demonstrated a stronger effect after adjustment for variation at the LPA locus (β [95% CI] [ln nmol/L], 0.089 [0.076–0.10]; P =3.8×10 -42 ). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044–0.28]; P =0.0071). Conclusions: In a large-scale genome-wide association study of Lp(a) levels, we identified APOH as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target. Abstract : Supplemental Digital Content is available in the text.